1. Field of the Invention
The present invention relates to method of producing a capsinoid compound by dehydrating condensation. The present invention also relates to a method for stabilizing a capsinoid compound. The present invention further relates to stabilized capsinoid compositions.
2. Discussion of the Background
Capsaicin ((E)-N-(4-hydroxy-3-methoxybenzyl)-8-methyl-6-nonenamide), the pungent ingredient of Capsicum annuum L., has physiological activities such as the suppression of obesity, promotion of energy metabolism, and the like. Due to its extremely strong pungent taste, however, capsaicin can be used only in a limited amount, and cannot be used as a food additive, a pharmaceutical product, and the like.
In recent years, Yazawa et al. have developed and reported a non-pungent cultivar of Capsicum annuum L., CH-19 Sweet, by fixing a non-pungent fruit over the years, which was selected from the fruits of a highly pungent cultivar CH-19, a native of Thailand (see, e.g., Yazawa, S.; Suetome, N.; Okamoto, K.; Namiki, T. J. Japan Soc. Hort. Sci., 1989, 58, 601-607).
CH-19 Sweet contains a large amount of capsinoids, which are free of a pungent taste. These capsinoids include capsiate, dihydrocapsiate, and nordihydrocapsiate, in the order of content, the first being the highest, which have the following structures.

These capsinoids have the same physiological activities as capsaicin and are free of a pungent taste. Accordingly, they may be usable as food additives or pharmaceutical products. However, production of capsinoids with high purity in a large amount from natural sources is limited, and a novel synthetic method for conveniently producing such capsinoids in a large amount has been desired.
To form an ester bond of a capsinoid, it is a general practice to condense vanillyl alcohol and a fatty acid derivative.
Vanillyl alcohol has two reaction sites of a primary hydroxyl group and a phenolic hydroxyl group. Since conventional esterification methods, such as a method of condensing vanillyl alcohol and an acid chloride of fatty acid in the presence of a base (see, e.g., Kobata, K.; Todo, T.; Yazawa, S.; Iwai, K.; Watanabe, T. J. Agric. Food Chem., 1998, 46, 1695-1697), permit reaction of the acid chloride with both the primary hydroxyl group and the phenolic hydroxyl group, the yield of the object capsinoid becomes lower.
For synthesis of capsinoids by a conventional esterification method, therefore, the phenolic hydroxyl group of vanillyl alcohol may be selectively protected. However, this requires protection and deprotection before and after esterification, thus unpreferably increasing the number of steps necessary for the production. Furthermore, such capsinoids are associated with a problem that they are unstable and easily decomposed during deprotection.
As a method for selectively reacting the primary hydroxyl group alone, the Mitsunobu reaction (see, e.g., Appendino, G.; Minassi, A.; Daddario, N.; Bianchi, F.; Tron, G. C. Organic Letters, 2002, 4, 3839-3841) and a method involving the use of LiClO4 (see, e.g., Bandgar, B. P.; Kamble, V. T.; Sadavarte, V. S.; Uppalla, L. S. Synlett, 2002, 735-738) can be mentioned. The former is defective in that triphenylphosphine oxide and reduced diethyl azodicarboxylate occur as co-products after the reaction, which makes purification difficult, and the latter did not permit reproduction of the yield described in the publication, though the experiment was faithfully repeated by the present inventors. Accordingly, neither of them are suitable for industrial practice.
In the meantime, the primary hydroxyl group alone can be selectively reacted by an esterification method using an enzyme. This method is considered to be suitable for industrial practice from the aspects of easily available reagents and convenient steps. Specific examples of the method using an enzyme include a method of condensation of vanillyl alcohol and a fatty acid using an immobilized enzyme Novozym 435 (manufactured by Novozymes), which is one kind of lipase, in an acetone solvent (see, e.g., JP-A-2000-312598). However, since the reaction using the enzyme is an equilibrium reaction with water produced during esterification, the reaction takes a long time and the yield is as low as about 60%. To increase the yield, one of the starting materials may be used in a large excess to shift the equilibrium toward the esterification. However, this approach necessitates a step of separating the starting material remaining after the reaction from the resultant product, making the step complicated. When molecular sieves are added as a dehydrating agent, the yield increases, but only up to about 80%, and the dehydrating agent needs to be removed by filtration. For reuse of the enzyme, the enzyme and the dehydrating agent need to be separated from the cake after the reaction.
Furthermore, capsinoids are unstable and are known to be decomposed by mere dissolution in an organic solvent (see, e.g., Sutoh, K.; Kobata, K.; Watanabe, T. J. Agric. Food Chem., 2001, 49, 4026-4030). Therefore, techniques for stable separation and preservation of the capsinoid after industrial production of the capsinoid, become necessary.